Interferons are divided into type I, II, and III. Type I IFNs (IFN-α and IFN-β) are most abundant in number, distribution, and expression. Also, they are highly conserved among mammals in both structure and function. IFN-α2 has been used in the treatment of cancer such as bladder cancer, hepatocellular carcinoma, and leukemia. IFN-α2 augments the suppressed immune functions in patients with head and neck squamous cell carcinoma (HNSCC). IFN-α2 initiated T and NK cell mediated cytotoxicity of tumor cells through IFNγ dependent and independent mechanisms. IFN-α2 enhances suppressed T cell cytotoxicity by stimulation of the perforin-granzyme B system (IFNγ dependent). Also, IFN-α2 induces the expression of perforin-granzyme B in NK cells (NK mediated cytotoxicity, IFNγ independent). In a preliminary study, IFN-α2 appears to be an effective immunostimulator and impacts the clinical outcome in tongue squamous cell carcinoma patients. IFN-α had been used in the treatment of chronic hepatitis C (CHC); nevertheless, IFN-α is relatively unstable and requires frequent parenteral administration. Pegylation of IFN-α, polyethylene glycol (PEG)-IFN-α, reduces in vitro activity but increase the stability and plasma half-life of IFN-α; therefore, PEG-IFN-α has replaced IFN-α in CHC treatment.